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Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology

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Abstract

The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells1. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells2 and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-γ in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-γ exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-γt and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-γt, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.

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Figure 1: IL-23-induced IL-17 and IFN-γ are required for H. hepaticus-mediated innate colitis.
Figure 2: IL-23-responsive innate lymphoid cells in inflamed colon are Thy1highSCA-1+ROR-γt+.
Figure 3: Thy1 high innate lymphoid cells drive H. hepaticus-induced innate intestinal inflammation.
Figure 4: ROR-γt-expressing Thy1 high innate lymphoid cells are required for anti-CD40-induced innate intestinal inflammation.

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Change history

  • 29 April 2010

    Small changes were made to the labelling of Figs 2b, 3b and 4d.

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Acknowledgements

We thank N. Rust for cell sorting; R. Stillion and M. Ziegler for histology; J. Langhorne for providing the AN18 hybridoma; S. Cobbold and H.Waldmann for the gift of the depleting anti-Thy1 and isotype control antibodies; UCB Celltech for providing the blocking anti-IL-17 and isotype control antibodies; O. Boulard and S. Kirchberger for technical assistance; and C. Arancibia for critically reading the manuscript. This work was supported by the Wellcome Trust (F.P. and K.J.M.), the Marie-Curie Network fellowship (IMDEMI, MRTN-CT2004-006532) (S.B., P.A.), the Philippe Wiener-Maurice Anspach foundation (S.B.), European Crohn’s & Colitis Organisation (ECCO) (S.B.), the European Commission research programme INFLA-CARE (EC contract no. 223151) (S.B. and P.A.) and a Wellcome Trust and Howard Hughes Medical Institute Exchange Programme grant (P.A., F.P. and D.R.L.).

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Contributions

S.B. and P.A. designed and performed the experiments. H.U. performed histology. I.I.I. and D.R.L. provided Rag-/-Rorc-/- mice and were involved in the experiments with this strain. S.B. wrote the manuscript with K.J.M. and F.P., and K.J.M. and F.P. directed the research.

Corresponding authors

Correspondence to Kevin J. Maloy or Fiona Powrie.

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Competing interests: Collaboration with Celltech.

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Supplementary Information

This file contains Supplementary Methods and References and Supplementary Figures 1-12 with legends. Please note that the Supplementary Methods and References were added on April 18, 2010. (PDF 1474 kb)

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Buonocore, S., Ahern, P., Uhlig, H. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010). https://doi.org/10.1038/nature08949

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